DYRK1A inhibition and cognitive rescue in a Down syndrome mouse model are induced by new fluoro-DANDY derivatives

作者：Neumann Fernanda; Gourdain Stephanie; Albac Christelle; Dekker Alain D; Bui Linh Chi; Dairou Julien; Schmitz Afonso Isabelle; Hue Nathalie; Rodrigues Lima Fernando; Delabar Jean M; Potier Marie Claude; Le Caer Jean Pierre; Touboul David; Delatour Benoit; Cariou Kevin; Dodd Robert H^*

来源：Scientific Reports, 2018, 8(1): 2859.

DOI：10.1038/s41598-018-20984-z

Inhibition of DYRK1A kinase, produced by chromosome 21 and consequently overproduced in trisomy 21 subjects, has been suggested as a therapeutic approach to treating the cognitive deficiencies observed in Down syndrome (DS). We now report the synthesis and potent DYRK1A inhibitory activities of fluoro derivatives of 3,5-di(polyhydroxyaryl)-7-azaindoles (F-DANDYs). One of these compounds (3-(4-fluorophenyl)-5-(3,4-dihydroxyphenyl)-1H-pyrrolo[2,3-b] pyridine, 5a) was selected for in vivo studies of cognitive rescuing effects in a standard mouse model of DS (Ts65Dn line). Using the Morris water maze task, Ts65Dn mice treated i.p. with 20 mg/kg of 5a performed significantly better than Ts65Dn mice treated with placebo, confirming the promnesiant effect of 5a in the trisomic mice. Overall, these results demonstrate for the first time that selective and competitive inhibition of DYRK1A kinase by the F-DANDY derivative 5a may provide a viable treatment strategy for combating the memory and learning deficiencies encountered in DS.

• 出版日期2018-2-12